Correct folding of newly synthesized proteins is assisted by molecular chaperones and folding catalysts, two unrelated groups of helper molecules. Chaperones suppress non-productive side reactions by stoichiometric binding to folding intermediates, whereas folding enzymes catalyze some of the multiple folding steps that enable proteins to attain their final functional configurations (Kern, G. et al. (1994) FEBS Lett. 348: 145-148). One class of folding enzymes, the peptidyl prolyl cis/trans isomerases (PPlases), isomerize certain proline imidic bonds in what is considered to be a rate limiting step in protein maturation and export. There are three sequence-unrelated families of PPIases, the cyclophilins, the FK506 binding proteins, and the newly characterized parvulin family (Rahfeld, J. U. et al. (1994) FEBS Lett. 352: 180-184).
The cyclophilins, were originally identified as major receptors for the immunosuppressive drug cyclosporin A (CsA) (Handschumacher, R. E. et al. (1984) Science 226: 544-547; Harding, M. W. et al. (1986) J. Biol. Chem. 261: 8547-8555), widely used in the prevention of tissue allograft rejection. Furthermore, cyclophilins are strongly implicated as the principle target for the immunosuppressive effects of CsA and its various derivatives. Members of the FK506 binding protein family are targets of the peptidomacrolide FK506, another immunosuppressive agent.
The third family of PPIases includes parvulin PPIase of E. coli, a low molecular mass, hydrophilic protein that has homology to PPIases of several other species of bacteria, yeast, and humans (Rahfeld, et al., supra). Gel filtration studies and enzyme assays indicate that parvulin functions as a monomer rather than as subunit in a protein complex. The human parvulin-like PPIase, Pin1, was isolated through its interaction with NIMA kinase, a protein essential for cell cycle progression in Aspergillus nidulans. Sequencing of the Pin1 gene revealed a putative nuclear localization signal, an amino-terminal protein binding domain (a WW motif), and a carboxy-terminal region with homology to parvulin PPIase (Lu, K. P. et al. (1996) Nature 380: 544-547). Pin1 protein co-localizes with NIMA kinase in the nuclear speckle, a key component of the nuclear scaffold which undergoes disassembly during mitosis. Pin1 as shown to have PPIase activity and to functionally substitute for ESS1, an essential protein in yeast, which was subsequently determined to be a PPIase of the parvulin family (Hanes, S. D. et al. (1995) Yeast 5: 55-72). Depletion of ESS1 in yeast causes mitotic arrest, whereas overexpression of Pin1 in HeLa cells induces arrest in the G2 phase of the cell cycle (Lu, et al. supra). The Drosophila melanogaster gene, dodo, also has homology to parvulin, exhibits PPIase activity, and is functionally interchangeable with ESS1 (Maleszka, R. et al. (1996) Proc. Natl. Acad. Sci. 93: 447-451). Thus, eukaryotic members of the parvulin family of PPIases appear to have integral roles in the control of cell cycle progression.
Discovery of proteins related to human parvulin-like proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions useful in diagnosis, prevention, and treatment of cancer and inflammatory conditions.